Well over a decade ago, we demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all HIV-infected individuals receiving clinically effective ART. In addition, we demonstrated that HIV continually replicates at low levels in chronically infected individuals who are consistently aviremic during prolonged periods of receiving ART. Based on the above findings and similar observations from other groups, the persistent viral reservoir has become a major impediment to the eradication of HIV in infected individuals receiving ART. Consequently, a major current thrust of HIV therapeutic research is the development of strategies to eliminate HIV reservoirs and to achieve a cure for HIV infection. Considering that a complete eradication of HIV is not currently feasible in the majority of infected individuals, even under the best of circumstances involving early initiation of therapy, new approaches aimed at containing viral replication are being considered. The aim is not necessarily to achieve complete eradication of the virus, but rather to boost HIV-specific immune responses or passively transfer anti-HIV antibodies and other immune related agents in order to keep plasma viremia in check upon discontinuation of ART. To address this issue, we recently launched a clinical trial entitled a phase I randomized, double-blind, placebo-controlled study of a multi-antigen DNA vaccine prime delivered by in vivo electroporation and a recombinant vesicular stomatitis virus (rVSV) booster vaccine in HIV-infected patients who began antiretroviral therapy during acute/early infection. This is a randomized, 2-arm (1:1, 15 patients per arm), double-blind, placebo-controlled trial evaluating the safety and efficacy of an HIV multi-antigen plasmid DNA vaccine prime, in combination with an interleukin-12 plasmid DNA adjuvant delivered in vivo by electroporation, and a rVSV vaccine boost in subjects receiving ART who initiated therapy during the acute/early phase of HIV infection. Study subjects were randomized to receive placebo or the multi-antigen HIV DNA vaccine at week 0, 4, 12, and 36 and the rVSV HIV gag booster vaccine at week 24 and 48. After the week 56 visit, all subjects will undergo treatment interruption to determine if the vaccination strategy resulted in a reduction of viral replication, as evidenced by blunted or absent rebound HIV plasma viremia. This clinical trial is now fully enrolled. Twenty study participants have already completed the vaccination phase of the study and have discontinued ART. Although the study remains blinded, we have begun extensive immunologic and virologic analyses on longitudinal specimens obtained from these study subjects. These analyses include a variety of laboratory assays that are designed to measure 1) immunologic responses of CD4+ and CD8+ T cell populations to the study vaccines; 2) the impact of vaccination on the persistent HIV reservoir in the CD4+ T cell compartment and on plasma viral rebound upon discontinuation of ART; and 3) identification of predictors and correlates of virologic control in the absence of ART. We expect data sets will be completed on all study participants by September 2016. Recent advances in antibody cloning technologies have led to the discovery of a number of highly potent and broadly neutralizing HIV-specific monoclonal antibodies from B cells of HIV-infected individuals. It has been shown that certain broadly neutralizing HIV-specific antibodies can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in animal models and a small number of HIV-infected viremic individuals. However, it has been unclear what in vivo effects these antibodies might have on plasma viral rebound in HIV-infected individuals following discontinuation of ART. Given that virtually all infected individuals who initiated ART during the chronic phase of infection experience plasma viral rebound upon cessation of therapy, it is of great interest to investigate whether a potent HIV-specific monoclonal antibody, such as VRC01, can prevent plasma viral rebound in infected individuals whose antiretroviral drugs have been discontinued. To address this issue, we have launched a clinical trial entitled an exploratory, open-label study of VRC01 in subjects with chronic HIV infection undergoing analytical treatment interruption. This is a single-arm, open-label study to examine the effect of VRC01 on plasma viral rebound in 30 HIV-infected individuals who initiated ART during the chronic phase of infection following discontinuation of therapy. All study participants receive infusions of VRC01 (40mg/kg) at study days 0, 14, 28, and monthly thereafter for up to 6 months. All study participants discontinue ART on day 3 and their plasma viremia is monitored every 2 weeks to evaluate the efficacy of VRC01 as determined by its effect on plasma viral rebound following discontinuation of ART. Additionally, the kinetics of the emergence of VRC01-resistant HIV and the development of anti-HIV immunity (i.e., cytotoxic T lymphocyte response) in the study participants will be studied. Currently, 5 subjects (total planned accrual of 30 subjects) are enrolled in our trial. We anticipate that the study will be fully enrolled by March 2016.